TY - JOUR
T1 - A native interactor scaffolds and stabilizes toxic Ataxin-1 oligomers in SCA1
AU - Lasagna-Reeves, C. A.
AU - Rousseaux, M. W.C.
AU - Guerrero-Munoz, M. J.
AU - Park, J.
AU - Jafar-Nejad, P.
AU - Richman, R.
AU - Lu, N.
AU - Sengupta, U.
AU - Litvinchuk, A.
AU - Orr, H. T.
AU - Kayed, R.
AU - Zoghbi, H. Y.
N1 - Publisher Copyright:
© 2015 eLife Sciences Publications Ltd. All rights reserved.
PY - 2015/5/19
Y1 - 2015/5/19
N2 - Recent studies indicate that soluble oligomers drive pathogenesis in several neurodegenerative proteinopathies, including Alzheimer and Parkinson disease. Curiously, the same conformational antibody recognizes different disease-related oligomers, despite the variations in clinical presentation and brain regions affected, suggesting that the oligomer structure might be responsible for toxicity. We investigated whether polyglutamine-expanded Ataxin1, the protein that underlies spinocerebellar ataxia type 1, forms toxic oligomers and, if so, what underlies their toxicity. We found that mutant ATXN1 does form oligomers and that oligomer levels correlate with disease progression in the Atxn1154Q/+ mice. Moreover, oligomeric toxicity, stabilization and seeding require interaction with Capicua, which is expressed at greater ratios with respect to ATXN1 in the cerebellum than in less vulnerable brain regions. Thus, specific interactors, not merely oligomeric structure, drive pathogenesis and contribute to regional vulnerability. Identifying interactors that stabilize toxic oligomeric complexes could answer longstanding questions about the pathogenesis of other proteinopathies.
AB - Recent studies indicate that soluble oligomers drive pathogenesis in several neurodegenerative proteinopathies, including Alzheimer and Parkinson disease. Curiously, the same conformational antibody recognizes different disease-related oligomers, despite the variations in clinical presentation and brain regions affected, suggesting that the oligomer structure might be responsible for toxicity. We investigated whether polyglutamine-expanded Ataxin1, the protein that underlies spinocerebellar ataxia type 1, forms toxic oligomers and, if so, what underlies their toxicity. We found that mutant ATXN1 does form oligomers and that oligomer levels correlate with disease progression in the Atxn1154Q/+ mice. Moreover, oligomeric toxicity, stabilization and seeding require interaction with Capicua, which is expressed at greater ratios with respect to ATXN1 in the cerebellum than in less vulnerable brain regions. Thus, specific interactors, not merely oligomeric structure, drive pathogenesis and contribute to regional vulnerability. Identifying interactors that stabilize toxic oligomeric complexes could answer longstanding questions about the pathogenesis of other proteinopathies.
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U2 - 10.7554/eLife.07558
DO - 10.7554/eLife.07558
M3 - Article
C2 - 25988806
AN - SCOPUS:84930648934
SN - 2050-084X
VL - 4
SP - 1
EP - 46
JO - eLife
JF - eLife
IS - MAY
M1 - e07558
ER -